Skip to main content

Advertisement

SpringerLink
Log in

A Tetramethylpyrazine Piperazine Derivate CXC137 Prevents Cell Injury in SH-SY5Y Cells and Improves Memory Dysfunction of Rats with Vascular Dementia

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

We investigated the effects of CXC137, a tetramethylpyrazine piperazine derivate, on cell damage induced by N-methyl-d-aspartate (NMDA) in human derived neuroblastoma cells (SH-SY5Y) and its effect on memory dysfunction of rats with vascular dementia. It was found that the presence of CXC137 increased SH-SY5Y cells viability by inhibition of cell apoptosis induced by NMDA. These effects of CXC137 were accompanied by increases of the antioxidant superoxide dismutase activity and the level of reduced glutathione, and a decrease of lipid peroxidation product, malondialdehyde. The presence of CXC137 also showed to produce strong inhibition of cellular lactate dehydrogenase leakage, cell apoptosis and intracellular calcium overload. In a vascular dementia rat model established by bilateral common carotid arteries occlusion, treatment with CXC137 from 2 to 35 day of post-operation significantly improves the motor performance, spatial learning and memory capability of rats in both the prehensile traction test and Morris water maze test, an effect that was companied by reductions of the animal glutamic acid levels and the degree of brain mitochondrial swelling. These results suggest that CXC137 can improve the memory dysfunction in dementia and thus has important therapeutic potential for the treatment of dementia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lee AY (2011) Vascular dementia. Chonnam Med J 47(2):66–71

    Article  PubMed Central  PubMed  Google Scholar 

  2. Levine DA, Langa KM (2011) Vascular cognitive impairment: disease mechanisms and therapeutic implications. Neurotherapeutics 8(3):361–373

    Article  PubMed  Google Scholar 

  3. Baskys A, Hou AC (2007) Vascular dementia: pharmacological treatment approaches and perspectives. Clin Interv Aging 2(3):327–335

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Wenthold RJ, Prybylowski K, Standley S, Sans N, Petralia RS (2003) Trafficking of NMDA receptors. Annu Rev Pharmacol Toxicol 43:335–358

    Article  CAS  PubMed  Google Scholar 

  5. Sans N, Wang PY, Du Q, Petralia RS, Wang YX, Nakka S, Blumer JB, Macara IG, Wenthold RJ (2005) mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nat Cell Biol 7(12):1179–1190

    Article  PubMed  Google Scholar 

  6. Cheng XC, Liu XY, Xu WF, Guo XL, Ou Y (2007) Design, synthesis, and biological activities of novel Ligustrazine derivatives. Bioorg Med Chem 15(10):3315–3320

    Article  CAS  PubMed  Google Scholar 

  7. Ou Y, Dong X, Liu XY, Cheng XC, Cheng YN, Yu LG, Guo XL (2010) Mechanism of tetramethylpyrazine analogue CXC195 inhibition of hydrogen peroxide-induced apoptosis in human endothelial cells. Biol Pharm Bull 33(3):432–438

    Article  CAS  PubMed  Google Scholar 

  8. Spasova M, Philipov S, Nikolaeva-Glomb L, Galabov AS, Milkova TS (2008) Cinnamoyl- and hydroxycinnamoyl amides of glaucine and their antioxidative and antiviral activities. Bioorg Med Chem 16(15):7457–7461

    Article  CAS  PubMed  Google Scholar 

  9. Hu XZ, Xu Y, Hu DC, Hui Y, Yang FX (2007) Apoptosis induction on human hepatoma cells Hep G2 of decabrominated diphenyl ether (PBDE-209). Toxicol Lett 171(1–2):19–28

    Article  CAS  PubMed  Google Scholar 

  10. Fang JH, Wang XH, Xu ZR, Jiang FG (2010) Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage. BMC Neurosci 11:31

    Article  PubMed Central  PubMed  Google Scholar 

  11. Deng T, Zhang L, Ge Y, Lu M, Zheng X (2009) Redistribution of intracellular calcium and its effect on apoptosis in macrophages: Induction by oxidized LDL. Biomed Pharmacother 63(4):267–274

    Article  CAS  PubMed  Google Scholar 

  12. Sheng B, Gong K, Niu Y, Liu L, Yan Y, Lu G, Zhang L, Hu M, Zhao N, Zhang X, Tang P, Gong Y (2009) Inhibition of gamma-secretase activity reduces Aβ production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: Implications for the treatment of Alzheimer’s disease. Free Radic Biol Med 46(10):1362–1375

    Article  CAS  PubMed  Google Scholar 

  13. Hwang YK, Jinhua M, Choi BR, Cui CA, Jeon WK, Kim H, Kim HY, Han SH, Han JS (2011) Effects of Scutellaria baicalensis on chronic cerebral hypoperfusion-induced memory impairments and chronic lipopolysaccharide infusion-induced memory impairments. J Ethnopharmacol 137(1):681–689

    Article  PubMed  Google Scholar 

  14. Singh DP, Chopra K (2013) Verapamil augments the neuroprotectant action of berberine in rat model of transient global cerebral ischemia. Eur J Pharmacol 720:98–106

    Article  CAS  PubMed  Google Scholar 

  15. Plaisier F, Bastide M, Ouk T, Pétrault O, Laprais M, Stolc S, Bordet R (2008) Stobadine-induced hastening of sensorimotor recovery after focal ischemia/reperfusion is associated with cerebrovascular protection. Brain Res 1208:240–249

    Article  CAS  PubMed  Google Scholar 

  16. Agrawal R, Mishra B, Tyagi E, Nath C, Shukla R (2010) Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res 61(3):247–252

    Article  CAS  PubMed  Google Scholar 

  17. Tota S, Kamat PK, Saxena G, Hanif K, Najmi AK, Nath C (2012) Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats. Behav Brain Res 226(1):317–330

    Article  CAS  PubMed  Google Scholar 

  18. He XL, Wang YH, Gao M, Li XX, Zhang TT, Du GH (2009) Baicalein protects rat brain mitochondria against chronic cerebral hypoperfusion-induced oxidative damage. Brain Res 1249:212–221

    Article  CAS  PubMed  Google Scholar 

  19. Baliga SS, Jaques-Robinson KM, Hadzimichalis NM, Golfetti R, Merrill GF (2010) Acetaminophen reduces mitochondrial dysfunction during early cerebral postischemic reperfusion in rats. Brain Res 1319:142–154

    Article  CAS  PubMed  Google Scholar 

  20. Nade VS, Kawale LA, Dwivedi S, Yadav AV (2010) Neuroprotective effect of Hibiscus rosa sinensis in an oxidative stress model of cerebral post-ischemic reperfusion injury in rats. Pharm Biol 48(7):822–827

    Article  PubMed  Google Scholar 

  21. Farkas E, Luiten PG, Bari F (2007) Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 54(1):162–180

    Article  CAS  PubMed  Google Scholar 

  22. Briede J, Duburs G (2007) Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries. Cell Biochem Funct 25(2):203–210

    Article  CAS  PubMed  Google Scholar 

  23. Adibhatla RM, Hatcher JF (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40(3):376–387

    Article  Google Scholar 

  24. Nita DA, Nita V, Spulber S, Moldovan M, Popa DP, Zagrean AM, Zagrean L (2001) Oxidative damage following cerebral ischemia depends on reperfusion—a biochemical study in rat. J Cell Mol Med 5(2):163–170

    Article  CAS  PubMed  Google Scholar 

  25. Lang D, Kiewert C, Mdzinarishvili A, Schwarzkopf TM, Sumbria R, Hartmann J, Klein J (2011) Neuroprotective effects of bilobalide are accompanied by a reduction of ischemia-induced glutamate release in vivo. Brain Res 1425:155–163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47(2):122–129

    Article  CAS  PubMed  Google Scholar 

  27. Rodrigues FP, Pestana CR, Dos Santos GA, Pardo-Andreu GL, Santos AC, Uyemura SA, Alberici LC, Curti C (2011) Characterization of the stimulus for reactive oxygen species generation in calcium-overloaded mitochondria. Redox Rep 16(3):108–113

    Article  CAS  PubMed  Google Scholar 

  28. Vesce S, Kirk L, Nicholls DG (2004) Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate. J Neurochem 90(3):683–693

    Article  CAS  PubMed  Google Scholar 

  29. Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N (2007) Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci Res 85(15):3206–3212

    Article  CAS  PubMed  Google Scholar 

  30. Sugawara T, Chan PH (2003) Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5(5):597–607

    Article  CAS  PubMed  Google Scholar 

  31. Lee DH, Kim CS, Lee YJ (2011) Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro. Food Chem Toxicol 49(1):271–280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Shandong Province Outstanding Young Scientists Research Award Fund Project (BS2010SW020) and the Natural Science Foundation of China (81373450). And we thank Hao Zhang for his research thesis.

Conflict of interest

The authors declared that they have no conflicts of interests concerning this article.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 Wen Hua Xi Road, Jinan, 250012, People’s Republic of China

    Hao Zhang, Xin-Yong Liu, Xiao-Ming Shi, Wen-Fang Wang & Xiu-Li Guo

  2. Shandong Academy of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China

    Rong Sun

  3. Department of Bio-function, Taishan Medical University, Tai’an, 271000, People’s Republic of China

    Xiao-Ming Shi

  4. Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK

    Lu-Gang Yu

Authors
  1. Hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin-Yong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-Ming Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lu-Gang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiu-Li Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiu-Li Guo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, H., Sun, R., Liu, XY. et al. A Tetramethylpyrazine Piperazine Derivate CXC137 Prevents Cell Injury in SH-SY5Y Cells and Improves Memory Dysfunction of Rats with Vascular Dementia. Neurochem Res 39, 276–286 (2014). https://doi.org/10.1007/s11064-013-1219-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1219-5

Keywords

Search

Navigation